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Background The 15q13.3 microdeletion is associated with several neuropsychiatric disorders, including autism and schizophrenia. Previous association and functional studies have investigated the potential role of several genes within the deletion in neuronal dysfunction, but the molecular effects of the deletion as a whole remain largely unknown. Methods Induced pluripotent stem cells, from 3 patients with the 15q13.3 microdeletion and 3 control subjects, were generated and converted into induced neurons. We analyzed the effects of the 15q13.3 microdeletion on genome-wide gene expression, DNA methylation, chromatin accessibility, and sensitivity to cisplatin-induced DNA damage. Furthermore, we measured gene expression changes in induced neurons with CRISPR (clustered regularly interspaced short palindromic repeats) knockouts of individual 15q13.3 microdeletion genes. Results In both induced pluripotent stem cells and induced neurons, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Furthermore, we observed global effects of the microdeletion on the transcriptome and epigenome, with disruptions in several neuropsychiatric disorder–associated pathways and gene families, including Wnt signaling, ribosome function, DNA binding, and clustered protocadherins. Individual gene knockouts mirrored many of the observed changes in an overlapping fashion between knockouts. Conclusions Our multiomics analysis of the 15q13.3 microdeletion revealed downstream effects in pathways previously associated with neuropsychiatric disorders and indications of interactions between genes within the deletion. This molecular systems analysis can be applied to other chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders.

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings. METHODS: In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (,100 kb or .100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions. RESULTS: Patients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values , .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5. CONCLUSIONS: The increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted., This work was supported by a joint grant from the United Kingdom Medical Research Council and GlaxoSmithKline (Grant No. G0701420) and the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley National Health Service (NHS) Foundation Trust and Institute of Psychiatry, King’s College London. This work presents independent research in part funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. This work was also supported by the Wellcome Trust Grant No. 086635 (JJHR); NIHR Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King’s College London (SC-W); a Marie Curie Intra-European Fellowship within the 7th European Community Framework Programme; European Commission Grant Agreement No. 115008); and Canada Research Chairs program

Background Large Copy Number Variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. However, given that these large CNVs each affect many genes directly and an often even larger number of genes indirectly, understanding the molecular mechanisms that connect these loci with the clinical phenotypes is a considerable challenge. Methods Using Hi-C for the genome-wide analysis of long-range chromosome interactions and ChIP-Seq for the analysis of regulatory histone marks we studied the epigenomic effects of the prominent large deletion CNV on chromosome 22q11.2, in a cohort of Lymphoblastoid Cell Lines (LCLs), and also replicated a subset of the findings in LCLs with the common large deletion CNV on chromosome 1q21.1. Results We found that, in addition to local and global gene expression changes, there are pronounced and multilayered effects on chromatin states, chromosome folding and topological domains of the chromatin that emanate from the large CNV locus. Regulatory histone marks are altered in the deletion proximal regions, and in opposing directions for activating and repressing marks. There are also significant changes of histone marks elsewhere along chromosome 22q and genome wide. Chromosome interaction patterns are weakened within the deletion boundaries and strengthened between the deletion proximal regions. We detected a change in the manner in which chromosome 22q folds onto itself, namely by increasing the long-range contacts between the telomeric end and the deletion proximal region. Further, the large CNV affects the topological domain that is spanning its genomic region. Finally, there is a widespread and complex effect on chromosome interactions genome-wide, i.e. involving all other autosomes, with some of the effect directly tied to the deletion region on 22q11.2. Discussion These findings outline novel principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity. Our work demonstrates that there are molecular mechanisms other than the gene expression changes that result from the alteration of the copy number of a given gene, that should be taken into account when studying this problem. Multiple molecular levels of control should be assayed and analyzed in an integrated fashion when studying this essential phenomenon of human genome biology and pathophysiology.